Neural stimulation is an essential method both in fundamental neurophysiological studies as well as in a number of clinical applications. While significant advances have been made in electrode design and stimulation approaches since the early days of electrical neural stimulation, the method is fundamentally unchanged and limited. This proposal presents a new paradigm to in vivo neural activation based on pulsed infrared light. Optical stimulation provides a contact-free, spatially selective, artifact-free method without incurring tissue damage that may have significant advantages over electrical methods for many diagnostic and therapeutic clinical applications. This technology development proposal in response to PA-04-006 (Neurotechnology research, development, and enhancement) is directed towards the optimization of this novel approach for peripheral as well as cortical neural activation. The proposal is designed to determine the physical and physiological basis for this novel neurotechnology as well as assess its potential for in vivo application. Towards this, we hypothesize that 1) pulsed laser light can be used to stimulate discrete populations of neural cells resulting in artifact free, spatially specific action potentials; 2) optical stimulation can be accomplished without causing damage to the neural tissue; and 3) the mechanism of this effect is a thermo-mechanical process resulting in activation of ion channels of neural cell membranes by releasing intracellular calcium. The specific aims of this proposal have been designed in a systematic manner to evaluate and assess safety, efficacy and mechanism of optical stimulation in direct comparison with electrical stimulation in peripheral as well as the central nervous system (motor cortex). To accomplish these goals, the specific aims are: Specific Aim (1): Evaluate laser parameters for effective and safe stimulation of peripheral nerves. Specific Aim (2): Determine the physiological and physical mechanisms of optical neural stimulation. Specific Aim (3): Assess and identify the laser parameters for effective and safe stimulation of cortical neural tissue. Specific Aim (4): Compare spatial specificity and efficacy of optical stimulation to electrical methods for the functional mapping of the motor cortex. Specific Aim (5): Demonstrate clinical safety and efficacy of optical neural stimulation in humans. By the end of the proposed period of the grant application, we will have arrived at a general consensus for the basis of optical neural stimulation, optimized laser parameters for optical nerve stimulation, determined limits of spatial resolution and shown the safety and efficacy of this method for peripheral nerve as well as cortical stimulation in animals as well as in early human preclinical trials.